Photodynamic therapy (PDT) of malignancies with hematoporphyrin derivative (HpD) has shown great promise for the treatment of early stages of choroidal melanoma, endobronchial cancer and lung cancer. However, HpD is known to be a complex and variable mixture of complex molecules. Activity is now focused on finding a single, chemically discrete photoactive localizer for use as a photosensitizer in this protocol. In screening candidate agents for use s sensitizers, it has been noted that photophysical properties of compounds measured in vitro in simple solutions are not reliable predictors of the behavior of the compounds as sensitizers in vivo. The microenvironment within cells and tissues in which the photodynamic agents partition influences their photoreactivity. The overall goal of this proposal is to develop new agents from the porphyrin class as site-specific photosensitizers for PDT. This will be accomplished through two specific tasks: (1) constituting and characterizing models of the heterogeneous microenvironment within cells with micelles, reverse micelles and gel microemulsions, and (2) evaluating the distribution and reactivity of porphyrins in these microenvironments. Three key features of photodynamic therapy with porphyrins will be probed on the molecular level within the model systems: (1) preferrential localization of porphyrins within discrete regions will be evaluated; the role of porphyrin structure and electronics in localization will be defined; (2) the influence of the local environment on the photoreactivity of porphyrins will be assessed, and (3) the nature and extent of localized changes induced in the models will be quantitatively and qualitatively examined. The results of these studies will advance the progress toward improved agents for PDT by providing a molecular level understanding of photoreactivity in microenvironments.